Heart failure is the leading cause of combined morbidity and mortality in the United States and other developed industrial nations. It remains an incurable disease process with an estimated two-year mortality of 30-50% for the patients with advanced disease. Growth hormone (GH) administration in patients with GH deficiency dramatically improved cardiac function and recent studies indicate beneficial effects of GH in patients with heart failure due to ischemic or idiopathic cardiomyopathy. Since the administration of growth hormone releasing hormone (GHRH) is the natural way to increase GH secretion, with no known side effects, GHRH may be the more beneficial treatment for human heart failure. Our primary objective in this Phase I proposal will be to generate synthetic protease resistant GHRH polypeptides that will have considerable longer half lives in serum as a means to develop a longer term therapy for human heart failure. This Phase I proposal will test the hypothesis that increased systemic levels of GH and IGF-I through the natural and physiological appropriate action of GHRH on the anterior pituitary may provide a long term solution for heart failure. Protease resistant GHRH polypeptides as a key hormone replacement therapy will enhance pulsatile secretion of GH by its natural secretagogue thus restoring cardiac contractility in mammalian heart failure models. Injection of protease resistant GHRH will entrain pulsatile GH secretion and enhance biosynthesis in older humans, the population that may experience increased frequency of heart failure. Heart failure in a mouse model of heart failure will be used to determine the role of novel GHRH protease resistant polypeptides on maintenance of cardiac mass and improved cardiac function with hormone treatment.